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The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer – a study protocol

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dc.contributor.authorUrsprung, Stephan
dc.contributor.authorMossop, Helen
dc.contributor.authorGallagher, Ferdia A.
dc.contributor.authorSala, Evis
dc.contributor.authorSkells, Richard
dc.contributor.authorSipple, Jamal A. N.
dc.contributor.authorMitchell, Thomas J.
dc.contributor.authorChhabra, Anita
dc.contributor.authorFife, Kate
dc.contributor.authorMatakidou, Athena
dc.contributor.authorYoung, Gemma
dc.contributor.authorWalker, Amanda
dc.contributor.authorThomas, Martin G.
dc.contributor.authorOrtuzar, Mireia Crispin
dc.contributor.authorSullivan, Mark
dc.contributor.authorProtheroe, Andrew
dc.contributor.authorOades, Grenville
dc.contributor.authorVenugopal, Balaji
dc.contributor.authorWarren, Anne Y.
dc.contributor.authorStone, John
dc.contributor.authorEisen, Tim
dc.contributor.authorWason, James
dc.contributor.authorWelsh, Sarah J.
dc.contributor.authorStewart, Grant D.
dc.contributor.orcidStewart, Grant D. [0000-0003-3188-9140]
dc.date.accessioned2021-11-22T14:45:39Z
dc.date.available2021-11-22T14:45:39Z
dc.date.issued2021-11-18
dc.date.submitted2021-04-08
dc.date.updated2021-11-22T14:45:39Z
dc.descriptionFunder: AstraZeneca (GB)
dc.description.abstractAbstract: Background: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). Methods: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0–1, cM0–1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. Discussion: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. Trial registration: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018–003056-21.
dc.identifier.doi10.17863/CAM.78332
dc.identifier.eissn1471-2407
dc.identifier.others12885-021-08965-4
dc.identifier.other8965
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330889
dc.languageen
dc.publisherBioMed Central
dc.subjectStudy Protocol
dc.subjectClinical trial protocol [MeSH]
dc.subjectClear cell renal cell carcinoma [MeSH]
dc.subjectPhase II clinical trial [MeSH]
dc.subjectBayesian adaptive trial
dc.subjectOlaparib [MeSH]
dc.subjectCediranib [MeSH]
dc.subjectDurvalumab [MeSH]
dc.subjectWindow-of-opportunity
dc.subjectNeoadjuvant therapy [MeSH]
dc.titleThe WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer – a study protocol
dc.typeArticle
dcterms.dateAccepted2021-11-04
prism.issueIdentifier1
prism.publicationNameBMC Cancer
prism.volume21
pubs.funder-project-idCancer Research UK Cambridge Centre (C9685/A25177)
pubs.funder-project-idNIHR Cambridge Biomedical Research Centre (BRC-1215-20014)
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1186/s12885-021-08965-4

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